Postsynaptic 5-HT2A receptors are widely distributed in both the central nervous system and elsewhere in the body. Activation of these receptors can affect:
– Sleep and arousal
– Sexual behavior
– Gut motility
– Vascular smooth muscle tone
Therefore, one might expect that some side effects of serotonergic antidepressants like insomnia, agitation, gastrointestinal distress, and sexual dysfunction may be related to activation of 5-HT2A receptors (Murphy et al., 2003).
What does research on variations (polymorphisms) in the 5-HT2A receptor show in terms of the risk of adverse effects with serotonergic antidepressants?
Polymorphisms of the 5-HT2A receptor gene (HTR2A)
The gene that codes for the 5-HT2A receptor is called HTR2A.
1. One polymorphism of HTR2A is called T102C (also written as 102 T/C). This notation simply means that at nucleotide position 102, instead of the usual T (thymine), there is a C (cytosine).
2. Another polymorphism of HTR2A is -1438G>A (at position -1438, there is an A instead of the more common G allele). This polymorphism is tested for in the commercial GeneSight® assay.
T102C polymorphism and side effects
Murphy et al. (2003):
1. Patients who were treated with paroxetine and had the C/C genotype of the T102C polymorphism were more likely to discontinue treatment with paroxetine due to side effects compared to others (i.e., those with the T/C or T/T genotypes).
How much more likely? 46.3% versus 16% of patients. If 30% more patients discontinue a medication due to side effects, isn’t that a huge difference?
The hazard ratio for discontinuation of paroxetine in this study was 3.0 for the C/C versus other genotypes (Murphy et al., 2004).
2. There was a statistically significant linear relationship between the number of C alleles in HTR2A and the probability of discontinuation of paroxetine due to side effects. Meaning that one C allele increased the probability of discontinuation due to side effects and two alleles increased the probability even more.
3. In addition to discontinuation due to side effects, the severity of side effects of paroxetine was also greater in patients with the C/C genotype.
4. Which side effects led to discontinuation of paroxetine treatment? Gastrointestinal (vomiting, nausea, diarrhea), somnolence, difficulty concentrating, agitation, sleep disturbance, and other side effects (dizziness, sweating, headache, sexual dysfunction).
5. Another thing that will help us to decide how useful it is to know whether or not our patient has a C/C or C/T genotype is to know how likely it is that he or she has a particular genotype, i.e., has C/C, C/T, or T/T genotype for this polymorphism.
In this study, C/C=33.6%, T/C= 51.6%, T/T=14.8%. So, about one-third of patients were at the highest risk of adverse effects. Note that even though in the general population the T allele is more common, in this clinical population with major depressive disorder, the C allele was more common.
6. This association between the C allele and more severe side effects does not apply to mirtazapine. In this study, HTR2A 102 T/C genotype had no effect on side effects of mirtazapine
-1438G/A polymorphism and side effects
The -1438G/G genotype of HTR2A has been found to be associated with a good response to SSRIs, especially to fluvoxamine, but with severe nausea in persons treated with paroxetine-treated (Kato et al., 2006)
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